This portion of the Program Project consists of two components: clinical studies and basic science studies. The specific aim of the clinical studies is to determine the effects of inhaled cocaine on the human nasal mucosa that contains the chemosensory receptors of the olfactory system. The specific aim of the basic science studies is to test the hypothesis that the microvillar cells, or "brush cells", found throughout the respiratory tract of humans and some mammals are chemoreceptors. Cocaine abuse is a rapidly-growing major health problem of epidemic proportions. Despite the wealth of data gathered on cocaine abuse, a significant gap in our knowledge exists: what are the histopathological effects of cocaine abuse on the human nasal mucosa and its unique population of olfactory receptor neurons? The olfactory mucosa contains several million olfactory receptor neurons, each of which is a primary sense cell--a bipolar neuron, whose cell body sits in the olfactory epithelium, that sends a dendrite into the nasal cavity and an axon to the olfactory bulb of the brain. These "naked neurons" sit right at the frontier of the central nervous system, and are the only nerve cells in the body that make direct contact with the environment. Consequently, they make direct contact with inhaled cocaine. The olfactory mucosa, unlike other nervous tissue, can be safely biopsied under local anesthesia and examined by electron microscopy, and will regenerate after removal. Therefore, this project will investigate the histopathology of cocaine abuse upon human olfactory receptors, which will serve as a major model system for the effects of cocaine and its adulterants upon the ultrastructure of components of the human central nervous system. The olfactory epithelium of humans and many mammals contains ciliated bipolar olfactory neurons and microvillar cells. Recent evidence indicates the microvillar cells are sensory neurons. Consequently, it seems that the human olfactory mucosa contains two morphologically distinct classes of olfactory receptor cell. When viewed by electron microscopy, the microvillar cells in the olfactory mucosa demonstrate a striking ultrastructural resemblance to the "brush cells" that are found in the trachea, bronchioles, and even alveoli deep in the lungs of humans, rats, and other mammalian species. Using the techniques of tracer studies, computer-generated three-dimensional reconstruction by high voltage electron microscopy, and immunocytochemistry, this project will test the hypothesis that the brush cells found throughout the respiratory system are chemoreceptive in nature.